A Study Evaluating the Safety and Efficacy of Second-Generation Tissue Engineered Vascular Grafts (TEVG2)

项目摘要 我们开发了一种专门用于先天性心脏病的组织工程化血管移植物（TEVG 手术TEVG是通过将自体骨髓来源的单核细胞接种到 可生物降解管状支架。一旦植入，支架降解，TEVG转化为 在结构和功能上都类似于天然血管的新生血管。第一次FDA的结果- 经批准的临床试验评估了TEVG在儿童中的使用，证明TEVG是第一个男性- 制造的血管管道，使其独特地适用于复杂的先天性心脏病的手术修复。 然而，心脏缺陷;这项研究的结果还表明，狭窄的发生率太高， 建议常规使用这项有前途的技术。后来，我们开发了一种改进的，第二种- 结合了用于抑制TEVG形成的两种合理设计的策略的一代TEVG 狭窄和工艺改进措施，组装TEVG，除了较新的不太严格， 进行TEVG血管成形术的标准。在此，我们提出了下一步的发展和翻译 TEVG：一项单机构、前瞻性、单臂、探索性-验证性临床试验，旨在 评估第二代TEVG在24例患者中的安全性和有效性，为期2年。在这 研究中，我们将评估第二代TEVG用作 单心室畸形患儿行改良Fontan手术的心外管道 我们将使用超声心动图和MRI连续监测所有移植受体2年以上的时间进程。我们 假设第二代TEVG的临界狭窄发生率显著降低 与我们之前FDA批准的试点研究中的原始TEVG结果相比。另外，我们假设 TEVG将随着时间的推移成长并转变为高度顺应的电容容器。我们将评估 Fontan循环中移植物顺应性对流经TEVG的流量、湍流和功率损失的影响。 具有生长能力的人造血管移植物的开发将使 明确的重建手术在早期的年龄，并减轻需要额外的手术， 到躯体过度生长（儿童生长超过其植入物的过程），从而改善 先天性心脏病患者。

PROJECT SUMMARY We developed a tissue engineered vascular graft (TEVG) designed specifically for use in congenital heart surgery. The TEVG is made by seeding autologous bone marrow-derived mononuclear cells onto a biodegradable tubular scaffold. Once implanted the scaffold degrades and the TEVG transforms into a neovessel that resembles a native blood vessel both in structure and function. Results of the first FDA- approved clinical trial evaluating the use of the TEVG in children demonstrated that the TEVG is the first man- made vascular conduit that grows making it uniquely suited for use in the surgical repair of complex congenital heart defects, however; results of this study also demonstrated that incidence of stenosis was too high to recommend routine use of this promising technology. We subsequently developed an improved, second- generation TEVG that incorporates both rationally designed strategies for inhibiting the formation of TEVG stenosis and process improvement measures for assembling the TEVG, in addition to newer less stringent criteria for performing TEVG angioplasty. Herein we propose the next step in the development and translation of the TEVG: a single-institution, prospective, single-armed, exploratory-confirmatory clinical trial designed to evaluate the safety and efficacy of the second-generation TEVG in 24 patients over a 2-year period. In this study, we will evaluate the short-term (2 year) safety and efficacy of a second-generation TEVG for use as an extracardiac conduit in children with single ventricle cardiac anomalies undergoing modified Fontan surgery. We will serially monitor all graft recipients over a 2-year time course using echocardiography and MRI. We hypothesize that the second-generation TEVG will have a significantly lower incidence of critical stenosis compared to the results of original TEVG in our previous FDA-approved pilot study. In addition, we hypothesize that the TEVG will grow and transform over time into a highly compliant capacitance vessel. We will evaluate the effect of graft compliance on flow, turbulence, and power loss across the TEVG in the Fontan circulation. The development of a man-made vascular graft with growth capacity would enable the performance of definitive reconstructive surgical procedures at an early age and mitigate the need for additional surgeries due to somatic overgrowth (the process by which a child outgrows their implant), thereby improving outcomes in patients with congenital heart disease.